The treatment of chronic and non-chronic pain is of great significance in medicine. There is a worldwide requirement for effective therapeutic methods for providing tailored and targeted treatment of chronic and non-chronic pain, this being taken to mean pain treatment which is effective and satisfactory from the patient's standpoint. This is clear from the large number of scientific papers relating to applied analgesia or to basic nociception research which have recently been published.
Conventional opioids such as morphine are highly effective in treating severe to extreme pain. However, the use thereof is limited by known side-effects, for example respiratory depression, vomiting, sedation, constipation and development of tolerance. Moreover, they are less effective in treating neuropathic or incidental pain, which is in particular experienced by tumor patients.
Opioids exert their analgesic effect by binding to membrane receptors belonging to the family of G protein-coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors has prompted hopes that subtype-specific opioids may have a effect/side-effect profile which differs from that of, for example, morphine. Further pharmacological investigations have now tentatively revealed the existence of various subtypes of these opioid receptors (μ1, μ2, κ1, κ2, κ3, δ1 and δ2). There are moreover further receptors and ion channels which play a substantial role in the system governing the genesis and transmission of pain. The NMDA ion channel plays a particularly important part as a substantial proportion of synaptic communication passes via this channel. This channel controls calcium ion exchange between the neuronal cell and its surroundings.
The development of the patch-clamp technique has made it possible to elucidate the physiological significance of ion channel-selective substances. It has thus been possible clearly to demonstrate the effect of NMDA antagonists on the influence of calcium ions within the cell. It has also been established that these substances themselves have their own antinociceptive potential (e.g. ketamine). One important fact is that their mode of action differs greatly from that of, for example, opiates, as NMDA antagonists act directly on the cell's calcium balance, which vitally determines the transmission of pain. For the first time, it is thus possible to treat neuropathic types of pain successfully.
Various NMDA antagonists, which in this case were tetrahydroquinoline compounds, have already been described in the articles J. Med. Chem. (1992) 35, 1954–1968, J. Med. Chem. (1992) 35, 1942–1953 and Med. Chem. Res. (1991) 1; 64–73 and the patent applications EP 386 839, WO 97/12879 A1, WO 98/07704 A1 and WO 98/42673 A1. Many possible indications, including inter alia pain therapy, were mentioned in these publications, especially in the patent applications. However, the efficacy and usability of these substances are as yet unclear and there is accordingly still a requirement for further substances.